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Mitsuhiro Yanagida:cutting apart mitosisWilliam Wells

Kyoto is the refined city — packedwith Buddhist temples and Shintoshrines — that Mitsuhiro Yanagidacalls home. Whereas the cherryblossoms in Tokyo’s Ueno Park haveto compete with boisterous karaokeand beer parties, in Kyoto the morelikely accompaniment is a Zengarden of raked gravel. As Yanagidawalks past a shrine, tucked into awooded hill behind KyotoUniversity, he spies the nearbymountains. It is these “deep woods,”he says, that have allowed the“fermentation” of his ideas — ideasthat have led him to anunprecedented understanding offission yeast mitosis.

“He’s been a major player in themolecular biology of mitosis in fissionyeast — the dominant figure in thatfield,” says Stanford University yeastgeneticist David Botstein. Reflectingthat dominance, Yanagida is nowPresident of the Molecular BiologySociety of Japan and was elected lastmonth as a foreign member of theUK’s Royal Society.

But biology was not a favoredcareer when he started studying atTokyo University in 1960. Then, hisstated ambition was to become adoctor. Soon, however, he wascaptivated by the new world ofmolecular biology. Mystifying andintriguing words had sprung into thevocabulary: words like ‘operator’,‘repressor’ and ‘gene’. “It soundedvery new for students bored withstudying biochemistry,” he says. “Itsounded very abstract and analytical.”

Others were unraveling thegenetic code but at TokyoUniversity in the 1960s the closestthat Yanagida could get to molecularbiology was a study of themembrane biophysics of the slime

mould, Dictyostelium. That led tothe use of electron microscopy,and in turn to the study of phagehead morphogenesis.

Using a combination of mutantsand antibodies Yanagida was able, forthe first time, to localize proteincomponents on phage heads andthus understand their assembly. Hehad started the project as a model

system for how DNA is packagedinto chromosomes, yet he was nocloser to understanding even thesimplified phage case: how phageDNA was ferried and folded into thetiny phage head. After a discussionwith a colleague at Kyoto University,and an analysis of two early paperson fission yeast (Schizosaccharomycespombe), he decided overnight toswitch to this less popular system.“It was an impulse decision, andthen you are stuck with it for thenext 20 years,” he says.

Newly introduced shuttle vectorsgave Yanagida a start with yeastmolecular genetics, and hedeveloped a technique for stainingDNA with DAPI. Together with thesuperior cytology of fission yeast, theDAPI gave him his first good look athis object of fascination:chromosomes. They have remained

central to his studies ever since.“Chromosome segregation is likeclassical nuclear physics,” he says.“It’s fundamental to understand cellmultiplication and differentiation.”

By 1984 Yanagida had isolated aprotein involved in chromosomestructure. After an exhaustivebiochemical screen, a student founda mutant defective in theDNA-unwinding enzymetopoisomerase II. The mutant failedto segregate its duplicatedchromosomes, which were sliced inhalf by the septum of the dividingyeast cell. Yanagida used reciprocaltemperature shifts to show that theenzyme was needed both tocondense chromosomes, and to allowfor their untangling at the end ofmitosis. He also figured that a screen

for more mutantswith the same ‘cut’phenotype mightyield otherchromatinproteins. Thusbegan his mosthighly successfulscreen.His first screenhad, however,

already paid off. In 1976 Paul Nursehad staked out temperature-sensitivefission yeast mutants, so Yanagidastarted by looking for cold-sensitivemutants. The result “was anear-miracle for us,” he recalls. Offour interesting mutants, one was αtubulin, another was β tubulin, andthe remaining two were importantchromatin proteins. The student whodid the screen, Tadashi Toda, “hadtremendously good eyes,” saysYanagida. “Since then we have had arelatively easy time convincingpeople that our genes are important.”

This was fortunate, for the cutscreen turned up a number of geneswhose function was harder to pindown. The genes encodedeverything from a kinesin to proteinsinvolved in sister chromatidcohesion, chromosome condensation,and protein destruction duringmitotic exit.

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Mitsuhiro Yanagida — contemplatinga life of leisure

Fitting those genes into theircorrect context has taken a lot ofwork. Yanagida’s approach to thiswork has been influenced by hislocation — starting with the choice offission yeast. “Working on a remoteisland, I thought it may be better towork on a more obscure organism,” hesays. And once that work was started,“we were quite happy to study thesemutants in an isolated fashion.”

But if the research was somewhatisolated, the interpretation of thatresearch was not. Yanagida travels asmuch as possible to discuss hisresults, and encourages his studentsand others to do the same. There aredifficulties in bridging thegap — language is one, and cultureanother. With the Meiji restoration,which started more than 100 yearsago, the Japanese mantra forreengagement with the West waswakon yosai — Japanese soul andWestern talent — but “wakon yosai isnot possible,” says Yanagida. Tocommunicate effectively, “you needto share the same soul.”Unfortunately for Japanese scientists,“it is basically impossible to behavethe same way in Japan and theWest,” he says. “But we [in Japan]must be part of the world of science.I hope the younger generation willtake more responsibility for that.”

Yanagida is ever vigilant of hisscientific progeny, many of whomhave moved to universities in the USor Europe, but he has another concerncloser to home. Mandatory retirementlooms in just five years’ time, soYanagida’s considerable intellect isnow focussed on an administrativerather than intellectual problem. “Ineed to be very inventive,” he says,“about how to continue being ascientist after retirement.” He mayadd to his three successful books, andcontinue to promote the Japan-basedjournal Genes to Cells, but most of allhe will stick with what he doesbest — deep contemplation of someof biology’s most difficult problems.

William Wells is a freelance writer based inSan Francisco, USA.

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These abstract images showingcrystals of histology stains wereproduced by Peter Whittaker at theHeart Institute, Good SamaritanHospital, Los Angeles, California,USA, and were runners-up in thisyear’s Current BiologyPhotomicrography Competition.

The top image is of picrosiriusred and the bottom image is of

haematoxylin. Both were viewedwith polarized light. These stainscan be used with polarized light forthe quantitative assessment ofcellular and subcellular structure intissues such as collagen and muscle.(For more details, see Whittaker P,Lasers Surg Med 1999, 25:198-206and Whittaker P, J Clin Laser MedSurg 1997, 15:261-267.)

Biology in pictures

Crystal clear